Preventing overdoses involving stimulants: the POINTS study protocol.

BACKGROUND: In recent years, overdoses involving illicit cocaine, methamphetamine, and other stimulants have increased in the U.S. The unintentional consumption of stimulants containing illicit fentanyl is a major risk factor for overdoses, particularly in Massachusetts and Rhode Island. Understanding the drug use patterns and strategies used by people who use stimulants (PWUS) to prevent overdose is necessary to identify risk and protective factors for stimulant and opioid-involved overdoses. Mixed-methods research with people who distribute drugs (PWDD) can also provide critical information into the mechanisms through which fentanyl may enter the stimulant supply, and the testing of drug samples can further triangulate PWUS and PWDD perspectives regarding the potency and adulteration of the drug supply. These epidemiological methods can inform collaborative intervention development efforts with community leaders to identify feasible, acceptable, and scalable strategies to prevent fatal and non-fatal overdoses in high-risk communities. METHODS: Our overall objective is to reduce stimulant and opioid-involved overdoses in regions disproportionately affected by the overdose epidemic. To meet this long-term objective, we employ a multi-pronged approach to identify risk and protective factors for unintentional stimulant and opioid-involved overdoses among PWUS and use these findings to develop a package of locally tailored intervention strategies that can be swiftly implemented to prevent overdoses. Specifically, this study aims to [1] Carry out mixed-methods research with incarcerated and non-incarcerated people who use or distribute illicit stimulants to identify risk and protective factors for stimulant and opioid-involved overdoses; [2] Conduct drug checking to examine the presence and relative quantity of fentanyl and other adulterants in the stimulant supply; and [3] Convene a series of working groups with community stakeholders involved in primary and secondary overdose prevention in Massachusetts and Rhode Island to contextualize our mixed-methods findings and identify multilevel intervention strategies to prevent stimulant-involved overdoses. DISCUSSION: Completion of this study will yield a rich understanding of the social epidemiology of stimulant and opioid-involved overdoses in addition to community-derived intervention strategies that can be readily implemented and scaled to prevent such overdoses in two states disproportionately impacted by the opioid and overdose crises: Massachusetts and Rhode Island.

A simple heuristic for allocating opioid settlement funding to reduce overdose mortality in the United States.

As resolution for opioid-related claims and litigation against pharmaceutical manufacturers and other stakeholders, state and local governments are newly eligible for millions of dollars of settlement funding to address the overdose crisis in the United States. To inform effective use of opioid settlement funds, we propose a simple framework that highlights the principal determinants of overdose mortality: the number of people at risk of overdose each year, the average annual number of overdoses per person at risk, and the average probability of death per overdose event. We assert that the annual number of overdose deaths is a function of these three determinants, all of which can be modified through public health intervention. Our proposed heuristic depicts how each of these drivers of drug-related mortality - and the corresponding interventions designed to address each term - operate both in isolation and in conjunction. We intend for this framework to be used by policymakers as a tool for identifying and evaluating public health interventions and funding priorities that will most effectively address the structural forces shaping the overdose crisis and reduce overdose deaths.

Pangenome Graphs.

Low-cost whole-genome assembly has enabled the collection of haplotype-resolved pangenomes for numerous organisms. In turn, this technological change is encouraging the development of methods that can precisely address the sequence and variation described in large collections of related genomes. These approaches often use graphical models of the pangenome to support algorithms for sequence alignment, visualization, functional genomics, and association studies. The additional information provided to these methods by the pangenome allows them to achieve superior performance on a variety of bioinformatic tasks, including read alignment, variant calling, and genotyping. Pangenome graphs stand to become a ubiquitous tool in genomics. Although it is unclear whether they will replace linearreference genomes, their ability to harmoniously relate multiple sequence and coordinate systems will make them useful irrespective of which pangenomic models become most common in the future.

Cruel and Unusual: Reforming Carceral Systems to Protect and Affirm Transgender and Gender-Diverse Communities.

Transgender and gender-diverse communities are disproportionately incarcerated in the USA. Incarcerated gender minority populations are detained within carceral systems constructed around a cisgender (gender identity matches sex assigned at birth) binary (only male and female identities recognized) understanding of gender. This leads to marginalizing experiences while perpetuating the extreme vulnerability individuals experience in the community. In order to address this cruel and unusual experience, carceral systems should undergo "whole-setting" reforms to protect and affirm transgender and gender-diverse populations. This includes ensuring access to gender-affirming clinical care that aligns with community health standards recommended by medical professional associations. Implementing gender-affirming reforms reduces security issues and will likely improve health outcomes providing mutual benefit for both correctional staff and gender minority populations. Given the current divisive political and social environment for gender minority populations in the USA, evidence-based person-centered reforms in corrections are needed now more than ever.

Multi-level influences on increased overdose risk behaviors during the COVID-19 pandemic among people who use drugs in Rhode Island: a qualitative investigation.

BACKGROUND: The ongoing COVID-19 pandemic has disproportionately affected structurally vulnerable populations including people who use drugs (PWUD). Increased overdose risk behaviors among PWUD during the pandemic have been documented, with research underscoring the role of influencing factors such as isolation and job loss in these behaviors. Here, we use qualitative methods to examine the impact of the COVID-19 pandemic and pandemic-related response measures on drug use behaviors in a sample of PWUD in Rhode Island. Using a social-ecological framework, we highlight the nested, interactive levels of the pandemic's influence on increased overdose risk behaviors. METHODS: From July to October 2021, semi-structured interviews were conducted with 18 PWUD who self-reported any increase in behaviors associated with overdose risk (e.g., increased use, change in drug type and/or more solitary drug use) relative to before the pandemic. Thematic analysis was conducted using a codebook with salient themes identified from interview guides and those that emerged through close reading of transcribed interviews. Guided by a social-ecological framework, themes were grouped into individual, network, institutional, and policy-level influences of the pandemic on drug use behaviors. RESULTS: Individual-level influences on increased overdose risk behaviors included self-reported anxiety and depression, isolation and loneliness, and boredom. Network-level influences included changes in local drug supply and changes in social network composition specific to housing. At the institutional level, drug use patterns were influenced by reduced access to harm reduction or treatment services. At the policy level, increased overdose risk behaviors were related to financial changes, job loss, and business closures. All participants identified factors influencing overdose risk behaviors that corresponded to several nested social-ecological levels. CONCLUSIONS: Participants identified multi-level influences of the COVID-19 pandemic and pandemic-related response measures on their drug use behavior patterns and overdose risk. These findings suggest that effective harm reduction during large-scale crises, such as the COVID-19 pandemic, must address several levels of influence concurrently.

Immune biomarkers and response to checkpoint inhibition of BRAFV600 and BRAF non-V600 altered lung cancers.

BACKGROUND: While 2-4% of lung cancers possess alterations in BRAF, little is known about the immune responsiveness of these tumours. METHODS: Clinical and genomic data were collected from 5945 patients with lung cancers whose tumours underwent next-generation sequencing between 2015 and 2018. Patients were followed through 2020. RESULTS: In total, 127 patients with metastatic BRAF-altered lung cancers were identified: 29 tumours had Class I mutations, 59 had Class II/III alterations, and 39 had variants of unknown significance (VUS). Tumour mutation burden was higher in Class II/III than Class I-altered tumours (8.8 mutations/Mb versus 4.9, P < 0.001), but this difference was diminished when stratified by smoking status. The overall response rate to immune checkpoint inhibitors (ICI) was 9% in Class I-altered tumours and 26% in Class II/III (P = 0.25), with median time on treatment of 1.9 months in both groups. Among patients with Class I-III-altered tumours, 36-month HR for death in those who ever versus never received ICI was 1.82 (1.17-6.11). Nine patients were on ICI for >2 years (two with Class I mutations, two with Class II/III alterations, and five with VUS). CONCLUSIONS: A subset of patients with BRAF-altered lung cancers achieved durable disease control on ICI. However, collectively no significant clinical benefit was seen.

The Lived Experience of Managing HIV and Chronic Pain: Qualitative Interviews with Patients and Healthcare Providers.

People living with HIV (PLWH) experience higher rates of comorbid chronic pain conditions compared to the general population. Managing HIV and chronic pain, two stigmatized health conditions, can exacerbate physical and psychological suffering. The current qualitative study was designed to increase our understanding of the experience of living with HIV and chronic pain. Twenty participants were recruited from a hospital-based immunology center to participate in individual in-depth qualitative interviews. The interviews focused on the experience of living with (or managing) chronic pain for PLWH. All interviews were audio recorded, transcribed and double-coded. Several themes emerged from our applied thematic analysis of the transcripts. The primary theme was that pain remained poorly managed among PLWH. Patients engaged in a variety of pain management strategies and described benefits from both traditional pain management interventions (e.g., pharmacology, physical therapy) as well as non-traditional approaches (e.g., medical marijuana, cannabidiol products, and spirituality). Other themes that emerged included barriers related to health insurance and the need to validate the patient pain experience. PLWH and chronic pain described compounding effects of managing two chronic health conditions, including perceived immune system over-activation, heightened awareness of illness, and negative mindset. More research is needed to improve care for those managing these often co-occurring health conditions.

How do US orthopaedic surgeons view placebo-controlled surgical trials? A pilot online survey study.

Randomised placebo-controlled trials (RPCTs) are the gold standard for evaluating novel treatments. However, this design is rarely used in the context of orthopaedic interventions where participants are assigned to a real or placebo surgery. The present study examines attitudes towards RPCTs for orthopaedic surgery among 687 orthopaedic surgeons across the USA. When presented with a vignette describing an RPCT for orthopaedic surgery, 52.3% of participants viewed it as 'completely' or 'mostly' unethical. Participants were also asked to rank-order the value of five different types of evidence supporting the efficacy of a surgery, ranging from RPCT to an anecdotal report. Responses regarding RPCTs were polarised with 26.4% viewing it as the least valuable (even less valuable than an anecdote) and 35.7 .% viewing it as the most valuable. Where equipoise exists, if we want to subject orthopaedic surgeries to the highest standard of evidence (RPCTs) before they are implemented in clinical practice, it will be necessary to educate physicians on the value and ethics of placebo surgery control conditions. Otherwise, invasive procedures may be performed without any benefits beyond possible placebo effects.

A Model to Study NMDA Receptors in Early Nervous System Development.

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that play critical roles in neuronal development and nervous system function. Here, we developed a model to study NMDARs in early development in zebrafish, by generating CRISPR-mediated lesions in the NMDAR genes, grin1a and grin1b, which encode the obligatory GluN1 subunits. While receptors containing grin1a or grin1b show high Ca2+ permeability, like their mammalian counterpart, grin1a is expressed earlier and more broadly in development than grin1b Both grin1a-/- and grin1b-/- zebrafish are viable. Unlike in rodents, where the grin1 knockout is embryonic lethal, grin1 double-mutant fish (grin1a-/-; grin1b-/-), which lack all NMDAR-mediated synaptic transmission, survive until ∼10 d dpf (days post fertilization), providing a unique opportunity to explore NMDAR function during development and in generating behaviors. Many behavioral defects in the grin1 double-mutant larvae, including abnormal evoked responses to light and acoustic stimuli, prey-capture deficits, and a failure to habituate to acoustic stimuli, are replicated by short-term treatment with the NMDAR antagonist MK-801, suggesting that they arise from acute effects of compromised NMDAR-mediated transmission. Other defects, however, such as periods of hyperactivity and alterations in place preference, are not phenocopied by MK-801, suggesting a developmental origin. Together, we have developed a unique model to study NMDARs in the developing vertebrate nervous system.SIGNIFICANCE STATEMENT Rapid communication between cells in the nervous system depends on ion channels that are directly activated by chemical neurotransmitters. One such ligand-gated ion channel, the NMDAR, impacts nearly all forms of nervous system function. It has been challenging, however, to study the prolonged absence of NMDARs in vertebrates, and hence their role in nervous system development, due to experimental limitations. Here, we demonstrate that zebrafish lacking all NMDAR transmission are viable through early development and are capable of a wide range of stereotypic behaviors. As such, this zebrafish model provides a unique opportunity to study the role of NMDAR in the development of the early vertebrate nervous system.

In from the cold: M-protein light chain glycosylation is positively associated with cold agglutinin titer levels.

BACKGROUND: Primary cold agglutinin disease (CAD) is a monoclonal antibody (M-protein) and complement-mediated chronic hemolytic disease process. Antibody glycosylation can play a role in both antibody half-life and complement fixation. Recently, M-protein light chain (LC) glycosylation has been shown to be associated with AL amyloidosis. We hypothesized that M-protein LC glycosylation is also associated with cold agglutinin (CA) titers and CA-mediated hemolysis. STUDY DESIGN AND METHODS: A cross-sectional study of patients undergoing CA titer evaluation underwent mass spectrometric analysis for M-proteins and M-protein LC glycosylation. A subset of serum samples also underwent evaluation for the ability to trigger cold hemolysis in vitro. M-protein and M-protein LC glycosylation rates were compared across CA titer groups, clinical diagnosis, direct antiglobulin testing (DAT) results, and cold in vitro hemolysis rates. RESULTS: Both M-protein and M-protein LC glycosylation rates significantly differed across CA titer groups with the highest rates in those with elevated CA titers. M-protein LC glycosylation occurred almost exclusively on IgM kappa M-proteins and was significantly associated with positive DAT results and a clinical diagnosis of CAD. Cold in vitro hemolysis was demonstrated in two patients who both had a CA titer of more than 512 but there was no significant association with CA titer group or M-protein LC glycosylation status. CONCLUSION: M-protein LC glycosylation is significantly associated with higher CA titer levels. Given the role that antibody glycosylation can play in antibody half-life and complement fixation, further studies are needed to clarify the effects of LC glycosylation within the context of CAD.

Outpatient clinical pharmacy practice in the face of COVID-19 at a cancer center in New York City.

PURPOSE: With the rapid spread of COVID-19 in New York City since early March 2020, innovative measures were needed for clinical pharmacy specialists to provide direct clinical care safely to cancer patients. Allocating the workforce was necessary to meet the surging needs of the inpatient services due to the COVID-19 outbreak, which had the potential to compromise outpatient services. We present here our approach of restructuring clinical pharmacy services and providing direct patient care in outpatient clinics during the pandemic. DATA SOURCES: We conducted a retrospective review of electronic clinical documentation involving clinical pharmacy specialist patient encounters in 9 outpatient clinics from March 1, 2020 to May 31, 2020. The analysis of the clinical pharmacy specialist interventions and the impact of the interventions was descriptive. DATA SUMMARY: As hospital services were modified to handle the surge due to COVID-19, select clinical pharmacy specialists were redeployed from the outpatient clinics or research blocks to COVID-19 inpatient teams. During these 3 months, clinical pharmacy specialists were involved in 2535 patient visits from 9 outpatient clinics and contributed a total of 4022 interventions, the majority of which utilized telemedicine. The interventions provided critical clinical pharmacy care during the pandemic and omitted 199 in-person visits for medical care. CONCLUSION: The swift transition to telemedicine allowed the provision of direct clinical pharmacy services to patients with cancer during the COVID-19 pandemic.

Long-term follow-up of individuals under community supervision who refused rapid HIV testing.

Many criminal justice-involved persons on probation or parole do not receive HIV testing despite being at an increased risk for infection and transmission. Between April, 2011 and May, 2012 in Baltimore, MD and Providence, RI, a two-group randomized controlled trial was conducted in order to examine the uptake of on-site rapid HIV testing compared to off-site referral-based HIV testing at a community clinic. Adults under community supervision were recruited to complete baseline assessments and then offered optional, free rapid-HIV testing. Of the 1263 participants who completed baseline measures, 566 declined HIV testing prior to randomization to the on-site testing at the Probation/Parole office or referral to off-site testing in a community health clinic. Follow-up data from 50 individuals who declined HIV testing were collected from September 2016-June 2017 and are examined in the present study. We describe the long-term outcomes of these 50 individuals in terms of HIV testing, HIV status, and frequencies of drug and sex risk behaviors.

Toxic and Physiological Metal Uptake and Release by Human Serum Transferrin.

An atomistic understanding of metal transport in the human body is critical to anticipate the side effects of metal-based therapeutics and holds promise for new drugs and drug delivery designs. Human serum transferrin (hTF) is a central part of the transport processes because of its ubiquitous ferrying of physiological Fe(III) and other transition metals to tightly controlled parts of the body. There is an atomistic mechanism for the uptake process with Fe(III), but not for the release process, or for other metals. This study provides initial insight into these processes for a range of transition metals-Ti(IV), Co(III), Fe(III), Ga(III), Cr(III), Fe(II), Zn(II)-through fully atomistic, extensive quantum mechanical/discrete molecular dynamics sampling and provides, to our knowledge, a new technique we developed to calculate relative binding affinities between metal cations and the protein. It identifies protonation of Tyr188 as a trigger for metal release rather than protonation of Lys206 or Lys296. The study identifies the difficulty of metal release from hTF as potentially related to cytotoxicity. Simulations identify a few critical interactions that stabilize the metal binding site in a flexible, nuanced manner.

Creation of a score to predict risk of high conscious sedation requirements in patients undergoing endoscopy.

BACKGROUND AND AIMS: The administration of intravenous conscious sedation to patients undergoing GI endoscopy carries a risk of cardiopulmonary adverse events. Our study aim was to create a score that stratifies the risk of occurrence of either high-dose conscious sedation requirements or a failed procedure. METHODS: Patients receiving endoscopy via endoscopist-directed conscious sedation were included. The primary outcome was occurrence of sedation failure, which was defined as one of the following: (1) high-dose sedation, (2) the need for benzodiazepine/narcotic reversal agents, (3) nurse-documented poor patient tolerance to the procedure, or (4) aborted procedure. High-dose sedation was defined as >10 mg of midazolam and/or >200 µg of fentanyl or the meperidine equivalent. Patients with sedation failure (n = 488) were matched to controls (n = 976) without a sedation failure by endoscopist and endoscopy date. RESULTS: Significant associations with sedation failure were identified for age, sex, nonclonazepam benzodiazepine use, opioid use, and procedure type (EGD, colonoscopy, or both). Based on these 5 variables, we created the high conscious sedation requirements (HCSR) score, which predicted the risk of sedation failure with an area under the curve of 0.70. Compared with the patients with a risk score of 0, risk of a sedation failure was highest for patients with a score ≥3.5 (odds ratio, 17.31; P = 2 × 10-14). Estimated area under the curve of the HCSR score was 0.68 (95% confidence interval, 0.63-0.72) in a validation series of 250 cases and 250 controls. CONCLUSIONS: The HCSR risk score, based on 5 key patient and procedure characteristics, can function as a useful tool for physicians when discussing sedation options with patients before endoscopy.

Falling Through the Cracks: Risk Factors for Becoming Lost to HIV Care After Incarceration in a Southern Jail.

Using a retrospective cohort analysis of inmates released from Dallas County Jail between January 2011 and November 2013, this study characterizes people living with HIV/AIDS (PLWHA) who are lost to care after release from jail. We used Kaplan-Meier analysis to estimate the risk of becoming lost to post-release HIV care and a Cox proportional hazards regression model to identify associated factors. The majority of individuals (78.2%) were men and 65.5% were black. Of the incarcerations that ended with release to the community, approximately 43% failed to link to community HIV care. Non-Hispanic Whites were more likely than Hispanics or Blacks to drop out of care after release. Individuals with histories of substance use or severe mental illness were more likely to become lost, while those under HIV care prior to incarceration and/or who had adhered to antiretroviral therapy (ART) were more likely to resume care upon release. Targeted efforts such as rapid linkage to care and re-entry residence programs could encourage formerly incarcerated individuals to re-engage in care.

The Utilization of Joint Mobilization As Part of a Comprehensive Program to Manage Carpal Tunnel Syndrome: A Systematic Review.

OBJECTIVE: The purpose of this review is to identify the role of joint mobilization for individuals with Carpal tunnel syndrome (CTS). METHODS: A systematic search of 5 electronic databases (PubMed, CINAHL, Scopus, Cochrane Central Register of Controlled Trials, and SPORTDiscus) was performed to identify eligible full-text randomized clinical trials related to the clinical question. Joint mobilization had to be included in one arm of the randomized clinical trials to be included. Two reviewers independently participated in each step of the screening process. A blinded third reviewer assisted in cases of discrepancy. The PEDro scale was used to assess quality. RESULTS: Ten articles were included after screening 2068 titles. In each article where joint mobilization was used, positive effects in pain, function, or additional outcomes were noted. In most cases, the intervention group integrating joint mobilization performed better than the comparison group not receiving joint techniques. CONCLUSION: In the articles reviewed, joint mobilization was associated with positive clinical effects for persons with CTS. No studies used joint mobilization in isolation; therefore, results must be interpreted cautiously. This review indicates that joint mobilization might be a useful adjunctive intervention in the management of CTS.

Defining a recovery-oriented cascade of care for opioid use disorder: A community-driven, statewide cross-sectional assessment.

BACKGROUND: In light of the accelerating and rapidly evolving overdose crisis in the United States (US), new strategies are needed to address the epidemic and to efficiently engage and retain individuals in care for opioid use disorder (OUD). Moreover, there is an increasing need for novel approaches to using health data to identify gaps in the cascade of care for persons with OUD. METHODS AND FINDINGS: Between June 2018 and May 2019, we engaged a diverse stakeholder group (including directors of statewide health and social service agencies) to develop a statewide, patient-centered cascade of care for OUD for Rhode Island, a small state in New England, a region highly impacted by the opioid crisis. Through an iterative process, we modified the cascade of care defined by Williams et al. for use in Rhode Island using key national survey data and statewide health claims datasets to create a cross-sectional summary of 5 stages in the cascade. Approximately 47,000 Rhode Islanders (5.2%) were estimated to be at risk for OUD (stage 0) in 2016. At the same time, 26,000 Rhode Islanders had a medical claim related to an OUD diagnosis, accounting for 55% of the population at risk (stage 1); 27% of the stage 0 population, 12,700 people, showed evidence of initiation of medication for OUD (MOUD, stage 2), and 18%, or 8,300 people, had evidence of retention on MOUD (stage 3). Imputation from a national survey estimated that 4,200 Rhode Islanders were in recovery from OUD as of 2016, representing 9% of the total population at risk. Limitations included use of self-report data to arrive at estimates of the number of individuals at risk for OUD and using a national estimate to identify the number of individuals in recovery due to a lack of available state data sources. CONCLUSIONS: Our findings indicate that cross-sectional summaries of the cascade of care for OUD can be used as a health policy tool to identify gaps in care, inform data-driven policy decisions, set benchmarks for quality, and improve health outcomes for persons with OUD. There exists a significant opportunity to increase engagement prior to the initiation of OUD treatment (i.e., identification of OUD symptoms via routine screening or acute presentation) and improve retention and remission from OUD symptoms through improved community-supported processes of recovery. To do this more precisely, states should work to systematically collect data to populate their own cascade of care as a health policy tool to enhance system-level interventions and maximize engagement in care.

Nucleated Red Blood Cells in Children With Sickle Cell Disease Hospitalized for Pain.

Acute chest syndrome (ACS) and transfusion requirements are common and difficult to predict during hospitalizations for acute vaso-occlusive episodes (VOE) among individuals with sickle cell disease (SCD). This study examined the relationship between nucleated red blood cell (NRBC) counts during hospitalization for VOE and development of ACS or transfusion requirement among children with SCD. Retrospective chart review was performed for 264 encounters of patients with SCD hospitalized for uncomplicated VOE who had NRBC count data at admission during a 5-year period. Multivariable logistic regression analysis was conducted to determine the relationship of admission and change in NRBC ([INCREMENT]NRBC) to ACS/transfusion requirement. Overall, 44 of 264 (16.7%) encounters resulted in ACS, transfusion, or both. Admission NRBC was not associated with development of ACS/transfusion requirement. Among 125 of 264 (47.3%) encounters in which a subsequent CBC was obtained, greater increases in NRBCs and greater decrease in hemoglobin were significantly associated with ACS/transfusion requirement (OR, 2.72; 95% CI, 1.16, 6.35; P=0.02 and OR, 2.52; 95% CI, 1.08, 5.89; P=0.03, respectively). Our finding that an increase in NRBC counts was associated with development of ACS/transfusion requirement suggests that [INCREMENT]NRBCs may represent a useful biomarker for predicting complications in children with SCD hospitalized for VOE.